Download Antipsychotics Antimanics Antidepressants

Psychoses
 Schizophrenia (split mind), i.e. splitting of perception
and interpretation from reality—hallucinations, inability
to think coherently.
 Paranoid states with marked persecutory or other kinds
of fixed delusions (false beliefs) and loss of insight into
the abnormality.
 Mania—elation or irritable mood, reduced sleep,
hyperactivity, uncontrollable thought and speech, may
be associated with reckless or violent behaviour.
 Depression—sadness, loss of interest and pleasure,
worthlessness, guilt, physical and mental slowing,
melancholia, self-destructive ideation.
 A common form of mood disorder is bipolar disorder with cyclically
alternating manic and depressive phases. The relapsing mood disorder may
also be unipolar (mania or depression) with waxing and waning course.
Antipsychotics
 (neuroleptic, ataractic,major tranquillizer) useful in
all types of psychosis, especially schizophrenia.
ANTIPSYCHOTIC DRUGS
(Neuroleptics)
CLASSIFICATION
Typical antipsychotics
1. Phenothiazines
 Chlorpromazine
 Triflupromazine
 Thioridazine
 Trifluoperazine
 Fluphenazine
2. Butyrophenones
 Haloperidol
 Trifluperidol
 Droperidol
3. Thioxanthenes
 Flupenthixol
Atypical antipsychotics
 Clozapine
 Olanzapine
 Quetiapine
 Risperidone
 Amisulpiride
Typical antipsychotics
Mechanism of action
 All typical antipsychotics have potent dopamine D2 receptor
blocking action.
 Blockade of D2 receptors to the temporal and prefrontal areas
constituting the ‘limbic system’ is responsible for the antipsychotic
action.
 Drugs which increase DA activity (levodopa, bromocriptine) induce
or exacerbate schizophrenia.
 Accordingly, blockade of DA overactivity in limbic area produces the
antipsychotic therapeutic effect as well as the extrapyramidal side
effects(parkinsonian adverse effects)
PHARMACOLOGICAL ACTIONS
CNS
 In normal individuals they produce ‘neuroleptic syndrome’indifference to surroundings, paucity of thought, psychomotor
slowing, emotional quietening, reduction in initiative and
tendency to go off to sleep from which the subject is easily
arousable.
 In a psychotic they reduce irrational behaviour, agitation and
aggressiveness and controls psychotic symptomatology.
Disturbed thought and behaviour are gradually normalized,
anxiety is relieved. Hyperactivity, hallucinations and delusions
are suppressed.
 Neuroleptics have potent antiemetic action (except motion
sickness).
PHARMACOLOGICAL ACTIONS
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CVS
Neuroleptics produce hypotension (primarily
postural) (α adrenergic blocking potency).
Reflex tachycardia
accompanies hypotension.
High doses produce Q-T prolongation
Arrhythmia
Endocrine
↑ prolactin (by blocking the inhibitory action of DA on
pituitary lactotropes. This may result in galactorrhoea
and gynaecomastia).
↓ gonadotropin (amenorrhoea and infertility)
ATYPICAL ANTIPSYCHOTICS
(Second generation)
Typical
Atypical
 Have potent dopamine D2
 Have weak D2 blocking but
receptor blocking property
 Produce extrapyramidal side
effects
 Treat only the positive
symptoms (hallucinations,
aggression, etc.)
potent serotonin receptors 5HT2 blocking activity
 Produce few/no extrapyramidal
symptoms
 Both positive and negative
(apathy, cognitive deficit,
withdrawal, etc). symptoms of
schizophrenia are improved
ATYPICAL ANTIPSYCHOTICS
Mechanism of action
 Most of the second generation agents appear to exert
part of their unique action through inhibition of
serotonin receptors (5-HT), but they are also a weak
dopamine D2 receptor antagonist
Actions
 Antipsychotic effects: “positive” symptoms, “negative”
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symptoms
Extrapyramidal symptoms (EPS): The secondgeneration
antipsychotics exhibit a lower incidence of EPS.
Antiemetic effects
Anticholinergic effects (blurred vision, dry mouth,
confusion, and inhibition of gastrointestinal and urinary
tract smooth muscle, leading to constipation and urinary
retention.
Other effects:
Blockade of α-adrenergic receptors causes orthostatic
hypotension and light-headedness.
Significant H1 blocking property is present.
USES
 Psychosis (Schizophrenia, acute mania)
 As antiemetic (useful in the treatment of
drug-induced nausea)
 Alcoholic hallucinosis
 Huntington’s disease
 Gilles de la Tourette’s syndrome
ADVERSE EFFECTS
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Extrapyramidal disturbances
These are the major ADR of typical antipsychotics.
Drug-related Parkinsonism— rigidity, tremor, hypokinesia,
mask like facies, shuffling gait; appears between 1–4 weeks of
therapy and persists unless dose is reduced.
Dystonia (sustained contraction of muscles leading to twisting,
distorted postures) mostly involving linguo-facial muscles —
grimacing, tongue thrusting, torticollis, locked jaw; occurs
within a few hours of a single dose or at the most in the first
week of therapy
Akathisia (motor restlessness, feeling of discomfort, apparent
agitation manifested as a compelling desire to move about, but
without anxiety, is seen in some patients between 1–8 weeks of
therapy:), and
Tardive dyskinesia - It occurs late in therapy, sometimes even
after withdrawal of the neuroleptic: manifests as purposeless
involuntary facial and limb movements like constant chewing,
pouting, puffing of cheeks, lip licking, choreoathetoid
movements.
Other ADRs
CNS
 Drowsiness, lethargy, mental confusion
 Tolerance to sedative effect may develop
 Increased appetite and weight gain
 Aggravation of seizures in epileptics
CVS
 Postural hypotension, palpitation, inhibition of ejaculation (due to α
adrenergic blockade)
 Cardiac arrhythmias
 Myocarditis
 Agranulocytosis
Anticholinergic
 Dry mouth, blurring of vision, constipation, urinary hesitancy
Endocrine
 Hyperprolactinemia (due to D2 blockade)
Weight gain -often occurs due to long-term antipsychotic therapy, sugar and lipids
may tend to rise.
Blue pigmentation of exposed skin
ADVERSE EFFECTS
(common for typical neuroleptics)
 Parkinsonism
 Malignant neuroleptic syndrome (marked rigidity,
immobility, tremor, hyperthermia, semiconsciousness,
fluctuating BP and heart rate). The syndrome lasts 5–
10 days after drug withdrawal and may be fatal.
 Hyperprolactinemia
ADVERSE EFFECTS
(common for atypical neuroleptics)
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QT prolongation
Arrhythmias
Agranulocytosis
Myocarditis
 Extrapyramidal and hyperprolactinaemic side
effects are minimal.
ANTIMANIC AND MOOD
STABILIZING DRUGS
(Drugs for bipolar disorder)
LITHIUM CARBONATE
 Lithium is the standard antimanic and mood
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stabilizing drug.
CNS
Lithium has practically no effects in normal
individuals;
Given to patients in acute mania, it gradually
suppresses the episode taking 1–2 weeks;
Continued treatment prevents cyclic mood changes.
 The therapeutic index of lithium is extremely low, and
lithium salts is very toxic.
Li+
Adverse effects
Side effects are common. Toxicity occurs at levels only marginally
higher than therapeutic levels.
1) Nausea, vomiting and diarrhoea
2) Thirst and polyuria
3) Fine tremors are noted even at therapeutic concentrations.
4) CNS toxicity -coarse tremors, giddiness, ataxia, motor
incoordination, nystagmus, mental confusion, slurred speech,
hyper-reflexia.
In acute intoxication these symptoms progress to muscle
twitchings, drowsiness, delirium, coma and convulsions. Vomiting,
severe diarrhoea, albuminuria, hypotension and cardiac arrhythmias
are the other features.
5) Contraindicated during pregnancy: foetal goiter, cardiac
abnormalities.
Li+ is excreted in sweat and saliva as well, and secreted in breast
milk.
Use
 Acute mania (inappropriate cheerfullness or
irritability, motor restlessness, high energy level,
nonstop talking, flight of ideas, little need for sleep
and progressive loss of contact with reality; sometimes
violent behaviour).
 Prophylaxis in bipolar disorder
ALTERNATIVES TO LITHIUM
 Approximately 30% patients of mania and bipolar
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disorder (especially rapidly cycling cases) show poor
response to lithium.
Sodium valproate
Carbamazepine
Lamotrigine
Atypical antipsychotics (now the first line drugs for
control of acute mania)
Antidepressants
 Depression is characterized by symptoms like sad
mood, loss of interest and pleasure, low energy,
worthlessness, guilt, psychomotor retardation or
agitation, change in appetite and/or sleep,
melancholia, suicidal thoughts, etc.
Antidepressants
 These are drugs which can elevate mood in depressive
illness.
 Practically all antidepressants affect mono-aminergic
transmission in the brain in one way or the other, and
many of them have other associated properties.
CLASSIFICATION
I. MAO-inhibitors
 Nonselective MAOIs
Nialamide
 Reversible inhibitors of MAO-A (RIMAs)
Moclobemide
II. Tricyclic antidepressants (TCAs) - NA + 5-HT reuptake inhibitors
Amitriptyline
Imipramine
Trimipramine
Clomipramine
III. Selective serotonin reuptake inhibitors (SSRIs)
 Fluoxetine
 Paroxetine,
 Sertraline
IV. Serotonin and noradrenaline reuptake inhibitors (SNRIs)
 Venlafaxine
V. Noradrenaline reuptake inhibitors (NRIs)
 Maprotiline
VI. Atypical antidepressants
 Trazodone,
 Mianserin,
 Mirtazapine,
 Tianeptine
MECHANISM OF ANTIDEPRESSANT DRUGS
 Most clinically useful antidepressant drugs potentiate,
either directly or indirectly, the actions of
norepinephrine and/or serotonin (5-HT) in the brain.
 Reuptake inhibition results in increased concentration
of the amines in the synaptic cleft in both CNS and
periphery → antidepressant action.
TRICYCLIC ANTIDEPRESSANTS
 These older compounds, in addition to uptake
blockade have direct effects on adrenergic, cholinergic
and histaminergic receptors, and are referred to as
‘first generation antidepressants,’ a group which also
includes MAOIs.
PHARMACOLOGICAL ACTIONS
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CNS
In normal individuals It induces a peculiar clumsy feeling,
tiredness, light-headedness, sleepiness, difficulty in
concentrating and thinking, unsteady gait. These effects
tend to provoke anxiety. There is no mood elevation; effects
are unpleasant.
In depressed patients After 2–3 weeks of continuous
treatment, the mood is gradually elevated, patients become
more communicative and start taking interest in self and
surroundings.
Thus, TCAs are not euphorients but only antidepressants.
Amitriptyline (sedative)are suitable for depressed
patients showing anxiety and agitation.
Imipramine (stimulant) are better for withdrawn and
retarded patients.
PHARMACOLOGICAL ACTIONS
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ANS
TCAs are potent anticholinergics— cause dry mouth, blurring
of vision, constipation and urinary hesitancy as side effect.
CVS
Tachycardia: due to anticholinergic and NA potentiating
actions.
Postural hypotension: due to inhibition of cardiovascular
reflexes and α1 blockade.
Arrhythmias
Tolerance and dependence
Tolerance develops gradually
Psychological dependence on these drugs is rare, because their
acute effects are not pleasant.
Physical dependence occure when used for long periods.
Gradual withdrawal is recommended due to withdrawal
phenomena
ADVERSE EFFECTS
 1. Anticholinergic: dry mouth, constipation, urinary
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retention, blurred vision, palpitation.
2. Sedation, mental confusion and weakness
3. Increased appetite and weight gain
4. Some patients receiving any antidepressant may
abruptly ‘switch over’ to a dysphoricagitated state or to
mania
5. Sweating and fine tremors
7. Postural hypotension
8. Sexual distress: especially delay or interference with
erection, ejaculation and occasionally with orgasm.
9. Cardiac arrhythmias
The major limitations of TCAs
 First generation antidepressants are:
 Frequent anticholinergic, cardiovascular and
neurological side effects.
 Relatively low safety margin. They are hazardous in
overdose; fatalities are common.
 Lag time of 2–4 weeks before antidepressant action
manifests.
 Significant number of patients respond incompletely
and some do not respond.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
 The safety and better acceptability of SSRIs has made
them the 1st line drugs in depression and allowed their
extensive use in anxiety, phobias, OCD and related
disorders.
ADVERSE EFFECTS of SSRIs
 Nausea
 Nervousness / Agitation
 Restlessness
 Insomnia
 Anorexia
 Sexual distress
 ‘Serotonin syndrome’ - agitation, restlessness, rigidity,
hyperthermia, delirium, sweating, twitchings followed
by convulsions can be precipitated when any
serotonergic drug (e.g. MAOIs) is taken by a patient
receiving SSRIs.
MAO INHIBITORS
 MAO is a mitochondrial enzyme involved in the
oxidative deamination of biogenic amines (Adr, NA,
DA, 5-HT). Two i forms of MAO have been identified:
 MAO-A inhibition reduces the breakdown of primarily
serotonin, norepinephrine
 MAO-B inhibition reduces the breakdown mainly of
dopamine
Nonselective MAO Inhibitors
Nialamide
 The nonselective MAO inhibitors elevate the mood of
depressed patients; in some cases it may progress to
hypomania and mania.
 Excitement and hypomania may be produced even in
nondepressed individuals.
 Nonselective MAO inhibitors inactivate the enzyme
irreversibly → effects last for 2–3 weeks after
discontinuation
Interactions
 These drugs interact with many food constituents and
drugs.
Cheese reaction
 Certain varieties of cheese, beer, wines, pickled meat and
fish, yeast extract contain large quantities of tyramine,
dopa, etc. In MAO inhibited patients → reaching into
systemic circulation → hypertensive crisis, cerebrovascular
accidents.
Cold and cough remedies
 They contain ephedrine or other sympathomimetics—
hypertensive reaction can occur
 Tricyclic antidepressants
 Barbiturates, alcohol, opioids, antihistamines
 Action of these drugs is intensified and prolonged.
Respiration may fail.
Reversible inhibitors of MAO-A
(RIMAs)
 MAO-A inhibitor with short duration of action; full
MAO activity is restored within 1–2 days of stopping
the drug.
 Dietary restrictions are not required.
 Adverse effects are nausea, dizziness, headache,
insomnia, rarely excitement and liver damage.
Chances of interaction with other drugs and alcohol
are remote, but caution is advised while co-prescribing
pethidine, SSRIs and TCAs.
 Use: Alternative to TCAs for severe depression and for
social phobia.
ATYPICAL ANTIDEPRESSANTS
 The atypical antidepressants are a mixed group of
agents that have actions at several different sites.
 They block presynaptic α2 receptors thereby
increasing release and turnover of NA in brain which
may be responsible for the antidepressant effect.